Our laboratory investigates molecular mechanisms that control liver proliferation. Liver specific protein, CCAAT/Enhancer Binding Protein alpha (C/EBPalpha), is a strong inhibitor of liver proliferation. In addition to growth arrest, C/EBPalpha supports differentiation-specific functions of the liver. We and others found that C/EBPalpha inhibits cell proliferation through multiple pathways. Two major pathways of C/EBPalpha -dependent growth arrest in the liver, inhibition of cdks and repression of E2F, are mediated via direct protein-protein interactions and are regulated by phosphorylation of C/EBPalpha. We mapped a single amino acid residue (Serl93), which is critical for C/EBPalpha growth arrest: de-phosphorylation of Serl93 or its mutation to Ala abolish the interactions of C/EBP( with cdks and with E2F-Rb complexes and blocks growth arrest. We identified a signal transduction pathway that regulates growth inhibitory activity of C/EBPalpha through de-phosphorylation of Serl93. The activation of PI3K/Akt pathway by insulin leads to de-phosphorylation of C/EBP( at Ser193, blocks growth inhibitory activity of C/EBPalpha and eliminates negative control of proliferation in the liver. Our recent studies show that insulin/PI3K/Akt pathway has several effects on the biological activities of C/EBPalpha. In addition to the block of growth inhibitory activity of C/EBP(, PI3K/Akt-mediated dephosphorylation of C/EBPalpha 1) increases a portion of C/EBPalpha that activates liver specific promoters and 2) creates a new activity of C/EBP( which is to accelerate cell proliferation. Thus, C/EBPalpha may inhibit or promote cell proliferation depending on its phosphorylation status. The major hypotheses of this application are that liver regulates biological functions of C/EBPalpha by phosphorylation and that the regenerating livers support proliferation and maintain differentiation-specific functions by phosphorylation-dependent switch of biological activities of C/EBPalpha.
Three Specific Aims are designed to test these hypotheses.
Specific Aim I investigates molecular mechanisms by which de-phosphorylated C/EBPalpha accelerates liver proliferation.
Specific Aim II examines the hypothesis that PI3K/Akt pathway increases the ability of C/EBP( to activate liver-specific promoters.
In Specific Aim III, we will examine the role of phosphorylation-dependent switch of biological functions of C/EBPalpha in vivo. C/EBPalpha-S193A knock-in mice will be generated and proliferative capacities of the liver will be examined in these animals.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
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Anderson, Richard A
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Baylor College of Medicine
Schools of Medicine
United States
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Jin, Jingling; Hong, Il-Hwa; Lewis, Kyle et al. (2015) Cooperation of C/EBP family proteins and chromatin remodeling proteins is essential for termination of liver regeneration. Hepatology 61:315-25
Jin, Jingling; Iakova, Polina; Breaux, Meghan et al. (2013) Increased expression of enzymes of triglyceride synthesis is essential for the development of hepatic steatosis. Cell Rep 3:831-43
Jiang, Yanjun; Jin, Jingling; Iakova, Polina et al. (2013) Farnesoid X receptor directly regulates xenobiotic detoxification genes in the long-lived Little mice. Mech Ageing Dev 134:407-15
Jiang, Yanjun; Iakova, Polina; Jin, Jingling et al. (2013) Farnesoid X receptor inhibits gankyrin in mouse livers and prevents development of liver cancer. Hepatology 57:1098-106
Jones, Karlie; Timchenko, Lubov; Timchenko, Nikolai A (2012) The role of CUGBP1 in age-dependent changes of liver functions. Ageing Res Rev 11:442-9
Jin, Jingling; Iakova, Polina; Jiang, Yanjun et al. (2011) The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation. Hepatology 54:989-98
Jones, Karlie; Jin, Bingwen; Iakova, Polina et al. (2011) RNA Foci, CUGBP1, and ZNF9 are the primary targets of the mutant CUG and CCUG repeats expanded in myotonic dystrophies type 1 and type 2. Am J Pathol 179:2475-89
Haefliger, Simon; Klebig, Christiane; Schaubitzer, Kerstin et al. (2011) Protein disulfide isomerase blocks CEBPA translation and is up-regulated during the unfolded protein response in AML. Blood 117:5931-40
Iakova, Polina; Timchenko, Lubov; Timchenko, Nikolai A (2011) Intracellular signaling and hepatocellular carcinoma. Semin Cancer Biol 21:28-34
Jin, Jingling; Wang, Guo-Li; Iakova, Polina et al. (2010) Epigenetic changes play critical role in age-associated dysfunctions of the liver. Aging Cell 9:895-910

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